WO 95/10514, WO 95/10515, WO 95/10516, published Apr. 20, 1995, WO 97/23478, published Jul. 3, 1997, and WO 98/57949, published Dec. 32, 1998, disclose tricyclic compounds useful for inhibiting farnesyl protein transferase.
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
This invention provides compounds selected from the group consisting of: 
In another embodiment, this invention provides a process for producing intermediate compound (4) 
comprising:
(a) dissolving compound (3) 
xe2x80x83in a solvent mixture comprising a suitable aprotic solvent (such as, for example, CH2Cl2, CHCl3 or benzene) and dimethylacetamide, said aprotic solvent to dimethylacetamide in a molar ratio in a range of about 1-10:1.0. Preferably said aprotic solvent to dimethylacetamide is in a molar ratio of 3.5:1.0;
(b) cooling the reaction mixture to a temperature of between about (xe2x88x92)10xc2x0 C. and about (+)10xc2x0 C.;
(c) adding about 10 to about 40 molar equivalents of thionyl bromide (i.e., SOBr2; Preferably the SOBr2 is freshly prepared (i.e., prepared and used within 72 hours) Still more preferably, the SOBr2 is prepared and used within 48 hours.
(d) stirring the reaction mixture at a temperature between about (xe2x88x92)10xc2x0 C. and about (+)40xc2x0 C., (in general the reaction is stirred for about 4 to about 10 hours, preferably about 4 hours);
(e) basifying the reaction mixture with an appropriate aqueous alkaline solution such as, a solution of NaOH, NaHCO3, NH4OH, and the like. Preferably the aqueous alkaline solution concentration is 1N; and
(f) extracting the resulting solution with a suitable organic solvent such as, for example, CH2Cl2, ethyl acetate, and the like.
In general, intermediate compound (4) obtained from the above process, is purified using techniques well known in the art, (e.g., flash silica gel column chromatography, HPLC, and the like).
The compounds of this invention are potent Farnesyl Protein Transferase inhibitors having good pharmacokinetic stability.
The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount (e.g. a therapeutically effective amount) of the tricyclic compounds listed below. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount (e.g. a therapeutically effective amount) of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount (e.g., a therapeutically effective amount) of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount (e.g. a therapeutically effective amount) of the below described compounds.
Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition or treatment being accomplished by the administration of an effective amount (e.g. a therapeutically effective amount) of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as Ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
As used herein, the following terms are used as defined below unless otherwise indicated:
MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
BOC-represents tert-butyloxycarbonyl;
CH2Cl2-represents dichloromethane;
CIMS-represents chemical ionization mass spectrum;
DEC-represents EDCl which represents 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride;
DMF-represents N,N-dimethylformamide;
Et-represents ethyl;
EtOAc-represents ethyl acetate;
EtOH-represents ethanol;
HOBT-represents 1-hydroxybenzotriazole hydrate;
IPA-represents isopropanol;
iPrOH-represents isopropanol;
Me-represents methyl;
MeOH-represents methanol;
MS-represents mass spectroscopy;
FAB-represents FABMS which represents fast atom bombardment mass spectroscopy;
HRMS-represents high resolution mass spectroscopy;
NMM-represents N-methylmorpholine;
Et3N-represents TEA which represents triethylamine;
t-BUTYL-represents xe2x80x94Cxe2x80x94(CH3)3;
THF-represents tetrahydrofuran;
FPT-represents Farnesyl Protein Transferase;
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
The compounds of this invention can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.